Levodopa (L-3,4 Diyhyrozyphenylalanine) is the gold standard therapy in the treatment of Parkinson disease, but its effectiveness decreases with chronic use. As it wears off, patients experience fluctuating and debilitating return of Parkinsonian symptoms, known as off episodes, which can occur for several hours per day. 

Clinical treatment goals focus on increasing on-time and managing or reducing off episodes, with pharmacological options to provide more continual dopaminergic stimulation as levodopa wears off. To this end, several agents are currently in development geared at the relief of off-time for patients with Parkinson. 

“One of the other things we’re looking at very intensively in research is finding new ways of delivering medicine,” said Fernando Pagan, MD, the medical director of the Georgetown University Hospital National Parkinsonism Foundation Center of Excellence. “We’re changing the way medications are delivered and the way we’re going to have therapeutics for our patients in the future.” 

Off symptoms, broadly known as levodopa-induced dyskinesia, can include 3 types of dyskinesia: peak-dose dyskinesia, wearing-off or off-period dyskinesia, and diphasic dyskinesia.1 Symptoms are marked by motor and nonmotor symptoms, such as bradykinesia, tremor, dystonia, cognitive impairment, mood swings, anxiety, panic attacks, and sleep disturbances. Risk factors for earlier onset of off episodes include early onset of disease, more severe disease at baseline, and higher levodopa dosage. 

Initial symptoms of off episodes can begin as early as just a few months after beginning treatment with levodopa. Most patients describe these symptoms as their greatest challenge in the management of the disease, with profound impacts on their functionality and quality of life. Off episodes may be somewhat predictable upon onset early in disease course, coming on in the mornings and correlating with the time between doses. Symptoms reappear, or worsen, prior to the next dose of levodopa and then improve once the dose is taken. As the disease inevitably progresses, however, the off episodes become less predictable and on-time is punctuated by the return of symptoms that can occur at any time of day and several times a day, correlating less with timing of the levodopa dose. 

Different Delivery Systems of Apomorphine 

Subcutaneous delivery of apomorphine, a dopamine agonist, is a clinically established therapy shown to be effective in reducing off-time in patients with motor fluctuations. The first double-blind, placebo-controlled, randomized test of this delivery of apomorphine was conducted in the phase 3 TOLEDO study.2 The subcutaneous infusion resulted in an absolute change in off-time, with achieved secondary endpoints of the percentage of patients with off-time reduction of at least 2 hours, absolute change in on-time without troublesome dyskinesia, change in oral levodopa and levodopa equivalent dose, change in the United Parkinson’s Disease Rating Scale (UPDRS) during on periods, and change in quality of life (using Parkinson’s Disease Questionnnaire-8). 

“The results of the TOLEDO study confirm what clinicians had observed and reported in uncontrolled studies for several decades: good efficacy and tolerability of apomorphine subcutaneous infusion,” principal investigator Regina Katzenschlager, MD, the head of the Department of Neurology at the Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders at Danube Hospital in Vienna, told NeurologyLive

Although the apomorphine infusion allows for fairly constant delivery to the bloodstream, 100% reduction in off-time remains elusive. Peter LeWitt, MD, MMedSc, editor-in-chief of Clinical Neuropharmacology, told NeurologyLive that without that full reduction, there may not be much to write home about. “In the recently published results of the TOLEDO study, using apomorphine infusion, patients improved who’d had motor fluctuations of up to 6 hours per day. They improved substantially, but their improvement was about 2 hours of the 6 hours of off-time. What about the rest of it?” said LeWitt, professor of neurology and psychiatry at Wayne State University School of Medicine. 

“There’s no doubt the drug achieved constant levels in the bloodstream and the brain. There’s no problem with absorption, because it’s being infused and taken up in the bloodstream, and yet the patient isn’t on. They still have off episodes throughout the day,” he said. “The same is true of Duopa, the continuous infusion of carbidopa and levodopa, to provide near-constant blood levels of levodopa, and yet patients only improve about one-third of their off-time, not the entire 100%.” 

A new drug application (NDA) with a January 29, 2019, the Prescription Drug User Fee Act deadline for a new mode of apomorphine delivery, APL-130277, was submitted by Sunovion to the FDA. APL-130277 will be a rescue therapy utilizing fast-acting sublingual delivery of an apomorphine-coated thin strip. The results of a phase 3, randomized, double-blind, placebo-controlled clinical trial with 109 patients showed significant mean reduction in the Movement Disorder Society-UPDRS Part III scores, with effects lasting from 30 to 90 minutes.3
 
The difference in UPDRS Part III scores between the treatment group and the control group from baseline to 30 minutes after dosing was 7.6 (P = .0002). The ease and accessibility of this quick delivery may be welcomed by patients for whom subcutaneous delivery of apomorphine presents unwanted side effects. Six of the 53 patients in the treatment group of the TOLEDO study withdrew due to treatment-related adverse events.2 

“Sublingual delivery seems to be effective, and it’s got a good data set of recorded results,” LeWitt said. “I’m not sure about a comparison with subcutaneous injection of apomorphine. I’m sure patients would prefer to have something as convenient as [sublingual delivery] and not have to use the injection form. The sacrifice is perhaps less efficacy, and maybe the speediness of its effect may be somewhat diminished.” 

“In the case of the sublingual apomorphine, the pharmacokinetics findings show that 15 to 30 minutes are when patients will start to get a substantial transfer of apomorphine, because the mucosa is not the fastest and also because the dose given may not hit the threshold for typical effect as quickly as hitting that threshold with subcutaneous administration,” he said. 

Inhaled Levodopa 

An NDA was filed for another potential rescue therapy, an inhaled powder form of levodopa known as CVT-301 (Inbrija), which was submitted by Acorda Therapeutics with an anticipated approval date of October 5, 2018. CVT-301 is intended for use during off episodes in between doses of oral levodopa. 

The application included data from the phase 3 SPAN-PD study,4 along with other long-term findings, which showed significant improvement in motor function for patients with Parkinson disease. Two doses of CVT-301 (84 and 60 mg, equivalent to 50- and 35-mg fine particle doses, respectively) were compared with placebo, with the change at week 12 in the UPDRS Part III score as the primary end point (–9.83 for 84-mg CVT-301 vs –5.91 for placebo; P = .009). 

CVT-301 was evaluated for safety in spirometry and diffusing capacity tests of the lung for carbon monoxide and showed no notable pulmonary safety signals. The inhaler was well tolerated by patients. 

“Nearly everyone with Parkinson [disease] can manage the device and make the necessary big breath to make the inhaler drug enter their lungs,” Donald Grosset, MD, the clinical director of UK Parkinson’s Excellence Network and a consultant neurologist at the Institute of Neurological Sciences at Queen Elizabeth University Hospital in Glasgow, United Kingdom, told NeurologyLive. “We were pleased to see this, as it might be thought that people with Parkinson, particularly when they are having a ‘dip’ in their motor control, would find it difficult to use the device, but this turned out not to be the case. It might be tried for early morning off episodes, rather than ‘later in the day’ ones.” 

Rapid delivery of levodopa has potential to become an effective rescue therapy for patients experiencing troublesome dyskinesia in need of quick relief. “The published findings of the pharmacokinetics of CVT-301 show that it gets into the bloodstream and gets to the brain very rapidly, and levodopa translates into a dopaminergic effect within 5 to 8 minutes,” LeWitt explained. 

New MAO-B and COMT Inhibitors 

Other mechanisms of action are being explored, in addition to new formulations of levodopa and apomorphine. The monoamine oxidase B (MAO-B) inhibitor safinamide (Xadago) has shown promise in the SETTLE study, and the third-generation catechol-O-methyltransferase (COMT) opicapone showed superiority in the BIPARK trials. 

Safinamide’s dual mechanism of action includes modulation of dopaminergic metabolism through selective reversible inhibition of MAO-B and blockade of voltage and use-dependent sodium channels that leads to inhibition of stimulated glutamate release. The action of the sodium channel blocker is important, because it does not influence physiological activity, avoiding depressant effects on the central nervous system. Accordingly, it does not have an effect on blood pressure or heart rate, expanding the patient populations who could tolerate this medication. Safinamide also has low potential for drug–drug interactions. 

In the SETTLE study,5 the daily oral dose of 50 or 100 mg of safinamide showed significant improvement in motor fluctuations, motor symptoms, nonmotor symptoms, and mobility compared with placebo. The study results suggested that the daily dose should be started at 50 mg and increased to 100 mg, based upon clinical evaluation of patient need. Used in tandem with levodopa, these data suggest that safinamide could be an appropriate choice as a first-line add-on therapy to levodopa. 

The SETTLE study showed that 100 mg of safinamide significantly increased mean daily on-time by 0.96 hours compared with placebo, meeting its primary endpoint of reducing troublesome dyskinesia. Long-term (24-month) analysis of safinamide show significant improvement in quality of life when used in tandem with levodopa. Importantly, positive motor and nonmotor improvements with safinamide have been proved for both the short term (6 months) and long term. 

Opicapone is a novel once-daily COMT inhibitor developed by Neurocrine Bio, which plans to submit an NDA with the FDA in the first half of 2019. Opicapone was shown to significantly decrease off-time compared with placebo in 2 pivotal phase 3 trials used for European approval, BIPARK-1 and BIPARK-2.6,7 

The BIPARK-I trial,6 which had 600 patients, showed that opicapone was noninferior to the earlier generation COMT inhibitor, entacapone (Comtan). The mean reduction in off symptoms was 96.3 minutes with entacapone compared with 116.8 minutes for 50-mg opicapone. In BIPARK-2,7 there was a 54.3-minute decline in off-time versus placebo for the 50-mg/day dose of opicapone. After 1 year of treatment, daily off-time was reduced by 126.3 minutes with opicapone.

Opicapone is thought to reduce off-time and extend on-time periods by decreasing the conversion rate of levodopa into 3-O-methyldopa, thereby increasing the plasma elimination half-life of levodopa and decreasing peak-trough variations. 

“Using a COMT inhibitor or a MAO-B inhibitor makes sense, because their mode of action is different in terms of extending the effects of levodopa,” said LeWitt. “We do that all the time—we’ve been doing that for 20 years. But the important thing about the medication effect is that it’s still not going to keep the patient on all the time. In fact, it may be no more effective than using one or the other.” 

Pharmacokinetic Limitations 

Dopaminergic stimulators and drugs that block the breakdown of dopamine in the brain have been proven to extend on-time and reduce off-time, but no medication or combination thereof has been proven to work all of the time to keep patients free of off episodes, especially as Parkinson disease progresses. The duration of effectiveness of levodopa seems to start diminishing from the onset of treatment and continues to diminish with duration of the disease. 

“While you can improve off-time pharmacologically, you might not be able to achieve 100%,” said LeWitt, author of “Levodopa Therapy for Parkinson’s Disease: Pharmacokinetics and Pharmacodynamics.8 “There may be more going on in the brain in Parkinson that prevents you from achieving near-constant on states from even the most continuous of dopaminergic stimulation, whether it’s with levodopa or a drug that mimics the effects of dopamine. All of the therapies we’ve thrown at this, ways to make the oral delivery of levodopa better, COMT inhibitor drugs, or any new MAO-B inhibitors, which partially block the breakdown of dopamine in the brain, are no better than drugs that have been around for more than 20 years.” 
LeWitt noted that in the studies that have been done, patients observe that they’ve experienced approximately 5 to 6 hours of off-time—but that may be the limit. Seemingly, he said, it cannot get better than improving 2 hours of off-time per day in a patient who has off-time for 5 to 6 hours per day on average. 

“It’s something that we occasionally simplify too much, to say ‘If only we had continuous dopaminergic stimulation or if we could bring the doses close enough together and use the COMT inhibitors and MAO-B inhibitors together and put this polypharmacy together, we could get constant dopaminergic stimulation.’ As if that’s the whole goal of helping the patient,” LeWitt continued. “And these therapies do work to some extent, but they do it imperfectly and there seems to be this glass ceiling, if you will, of keeping the patient fully on all the time that just can’t be achieved with current therapeutics.” 

Implications of Elusive On-Time Constancy 

Trials to establish the efficacy of established medications utilizing perhaps more efficient delivery systems have so far failed to prove complete reduction in off-time. 

“There’s a lot that isn’t logical about it, or conceptually, we have the wrong message that off-time is always a deficiency of dopaminergic stimulation to be improved by better delivery of drugs or blocking the breakdown of drugs we currently use,” said LeWitt. To him, the emerging story has been that the emergence of Parkinsonian symptoms can be, and is, a complex tale. 
“You can also criticize the studies, like the TOLEDO study, that maybe they didn’t [administer] enough apomorphine in the dosing with levodopa, to try to explain why the effect was as limited as it was. But that might not be the right answer to it,” LeWitt said. “It might just be that there’s some black box in the brain that fails to respond fully to continuous dopaminergic stimulation to relieve all of the Parkinsonian symptoms. I’m thinking more and more that it might be something we’ve yet to learn about this disorder, that as the disease goes by the responses to dopaminergic stimulation may fluctuate in a manner that doesn’t really suggest what to do about it now.” 

Disease progression can likely be implicated in the decreasing effectiveness of levodopa and the increasing incidence of off episodes that, at a clinical level, seem to take place simultaneously with progression. Inability to remain in an on state, even with constant dopaminergic stimulation, is a hallmark of disease progression. Duration of response to therapies can explain corresponding effectiveness of treatment. 

“The long duration of response essentially describes the initial state of responsiveness to levodopa, which is many hours, if not days, of benefit from a very short-acting drug that nonetheless transduces its benefits in a manner that goes beyond simply generating dopamine, which has a very rapid turnover in the brain,” LeWitt said. 

“What happens over time, at least conceptually, is that the long-duration response turns into the short-duration response, which is sort of a dose-by-dose effect, where not producing dopamine means the patient is off,” he added. “But having lost that long duration response, it may be that a number of other phenomena that are part of that are also lost. It could be that progression of the disease includes some mechanism whereby patients cannot achieve constancy from constant dopaminergic stimulation. But that isn’t really part of our current understanding, or dogma, about what progression is.” 
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